Proteome atlas for mechanistic discovery and risk prediction of diabetic retinopathy

Shaopeng Yang, Zhuoyao Xin, Ruilin Xiong, Ziyu Zhu, Huangdong Li, Yanping Chen, Zhenghao Zhong, Lanqi Du, Lisa Zhuoting Zhu, Xianwen Shang, Wenyong Huang, Lei Zhang, Shida Chen, Chang He, Shaoying Tan, Mingguang He, Nathan Congdon, Jost B. Jonas, Yih-Chung Tham (), Ching-Yu Cheng () and Wei Wang ()
Additional contact information
Shaopeng Yang: Guangdong Provincial Clinical Research Center for Ocular Diseases
Zhuoyao Xin: Department of Biomedical Engineering, Johns Hopkins University
Ruilin Xiong: Guangdong Provincial Clinical Research Center for Ocular Diseases
Ziyu Zhu: Guangdong Provincial Clinical Research Center for Ocular Diseases
Huangdong Li: Guangdong Provincial Clinical Research Center for Ocular Diseases
Yanping Chen: Guangdong Provincial Clinical Research Center for Ocular Diseases
Zhenghao Zhong: Guangdong Provincial Clinical Research Center for Ocular Diseases
Lanqi Du: Guangdong Provincial Clinical Research Center for Ocular Diseases
Lisa Zhuoting Zhu: Centre for Eye Research Australia, Royal Victorian Eye and Ear Hospital
Xianwen Shang: School of Optometry, The Hong Kong Polytechnic University
Wenyong Huang: Guangdong Provincial Clinical Research Center for Ocular Diseases
Lei Zhang: Clinical Medical Research Center, Children’s Hospital of Nanjing Medical University
Shida Chen: Guangdong Provincial Clinical Research Center for Ocular Diseases
Chang He: Guangdong Provincial Clinical Research Center for Ocular Diseases
Shaoying Tan: School of Optometry, The Hong Kong Polytechnic University
Mingguang He: Guangdong Provincial Clinical Research Center for Ocular Diseases
Nathan Congdon: Guangdong Provincial Clinical Research Center for Ocular Diseases
Jost B. Jonas: Rothschild Foundation Hospital, Institut Français de Myopie
Yih-Chung Tham: Singapore Eye Research Institute, Singapore National Eye Centre
Ching-Yu Cheng: Singapore Eye Research Institute, Singapore National Eye Centre
Wei Wang: Guangdong Provincial Clinical Research Center for Ocular Diseases

Nature Communications, 2025, vol. 16, issue 1, 1-21

Abstract: Abstract Proteomics offers an unprecedented opportunity to characterize and predict diabetic retinopathy (DR) with minimal invasiveness. Here we examine this in 10,873 individuals with (pre)diabetes from two ethnically distinct cohorts. By simultaneous profiling of ~3000 proteins, we identify 668 associations with mechanistically plausible directionality that constitute a comprehensive DR proteomic landscape with linkages to retinal tomographic structure and genetic predisposition, pointing to established and novel biological pathways conferring DR risk. Integrating DR proteomic profile markedly improves predictive performance beyond clinical and genetic predictors, with plexin B2, growth differentiation factor 15, and renin emerging as top proteins validated across cohorts and linked to retinal microvascular degeneration in Guangzhou Diabetic Eye Study (GDES) based on SS-OCTA. A parsimonious panel of these three proteins alone achieves comparable performance in predicting DR development and progression, while renin is confirmed as a causal promoter through genetic analyses. Our findings highlight the potential of large-scale proteomics in elucidating DR pathogenesis and advancing biomarker discovery, with broad implications for early detection and intervention.

Date: 2025
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DOI: 10.1038/s41467-025-64634-1

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